Use of an α-tocopherol phosphate or a derivative thereof for preparing cosmetic, dermatological or pharmaceutical compositions, and compositions thereby obtained

ABSTRACT

The present invention relates to the use of an α-tocopherol phosphate, especially in its dl or d form, or an ester thereof, of the general formula ##STR1## in which: R 1  is a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or an α-tocopheryl radical; and R 2  is a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, such as a methyl or ethyl radical in particular, or an oxyethylene chain of the formula ##STR2## in which R 3  and R 4  independently are a hydrogen atom or a methyl radical and n is an integer greater than or equal to 1, or a salt thereof, for preparing a pharmaceutical, dermatological or cosmetic composition for the prevention or treatment of allergic manifestations such as skin allergy or bronchial asthma, or inflammatory manifestations, or for the prevention or treatment of the harmful effects of free radicals.

This application is a division of application Ser. No. 07/917,142, filedJul. 31, 1992, now U.S. Pat. No. 5,387,579.

The present invention relates in general terms to the use of anα-tocopherol phosphate, or an ester thereof, or a salt of thesecompounds, for preparing pharmaceutical, cosmetic or dermatologicalcompositions with antiallergic or antiinflammatory activity or for theprevention or treatment of the harmful effects of free radicals, and topharmaceutical, cosmetic or dermatological compositions withantiallergic or anti-inflammatory activity or for the prevention ortreatment of the harmful effects of free radicals, in which saidcompound is incorporated.

It is known that vitamin E has the common name of α-tocopherol inparticular (see Merck Index, 10th edition, reference 9832, page 1437).

α-Tocopherol occurs in the natural state in numerous plants, usuallywith other compounds such as β-tocopherol and γ-tocopherol.

It is also known that α-tocopherol exists in both the dl and d forms.

α-Tocopherol is essentially used for controlling vitamin E deficienciesor as a nutritional factor, especially for controlling muscledegeneration.

It is also used as an antioxidant, but at very specific doses.

α-Tocopherol esters have also been described, in particular thesuccinate, the nicotinate or the acetate (Merck Index, 10th edition,references 9832, 9833, page 1437). The synthesis of α-tocopherol acetateis also described in U.S. Pat. No. 2,723,278 and that of other esters isdescribed in the document J. Amer. Chem. Soc. (1943) 65, 918-924.

dl-α-Tocopherol phosphate is also known (see P. KARRER et al., Helv.Chim. Acta (1940) 23, 1137-8), as is its action on muscle metabolism(see J. Biol. Chem. 1942, 146, pages 309-321). Another documentdescribes the biological role as an antioxidant on brain tissue (Biol.Antioxidants Trans., 1st Conf., 1946, pages 61-62). An anticoagulantaction through an action on the polymerization of fibrin has also beendescribed (Can. J. Biochem. and Physiol. 1959, 37, pages 501-505). Anantimicrobial action in vitro on B. subtilis and S. aureus has also beendescribed (Naturwissenschaften 1960, 47, page 17).

In another connection, German patent application A-3 416 209 describesthe use of creams containing vitamin E for the treatment and preventionof inflammatory processes. By contrast, Berkenkopf and Lutsky havedescribed that the injection of vitamin E into rats causes a chroniclocalized inflammation (Agents Actions 1979, 9, (4), 350-357).

Thus the action of vitamin E on inflammation is controversial.

It has now been discovered, totally surprisingly and unexpectedly, thatα-tocopherol phosphate, especially in its dl or d form, or an esterthereof, of the general formula ##STR3## in which: R₁ is a hydrogenatom, an alkyl radical having from 1 to 4 carbon atoms, such as themethyl or ethyl radical in particular, or an α-tocopheryl radical; and

R₂ is a hydrogen atom or an alkyl radical having from 1 to 4 carbonatoms, such as a methyl or ethyl radical in particular, or R₂ O is anoxyethylene chain of the formula ##STR4## in which R₃ and R₄independently are a hydrogen atom or a methyl radical and n is aninteger greater than or equal to 1

or a salt thereof, can be used for preparing a pharmaceutical,dermatological or cosmetic composition for the prevention or treatmentof allergic manifestations such as skin allergy or bronchial asthma, orinflammatory manifestations, or else for the prevention or treatment ofthe harmful effects of free radicals.

Thus the object of the present invention is to solve the new technicalproblem which consists in providing an active substance having a goodantiallergic activity, especially for the prevention or treatment ofskin allergy or bronchial asthma, or a good antiinflammatory activity,or else a preventive or curative activity against the harmful effects offree radicals, in particular by topical or general administration,thereby constituting a valuable active ingredient for preparingcosmetic, dermatological or pharmaceutical compositions.

The present invention solves this new technical problem satisfactorilywith a particularly simple solution which can be used on the industrialscale.

Thus, according to a first feature, the present invention covers the useof an α-tocopherol phosphate, especially in its dl or d form, or anester thereof, of the general formula ##STR5## in which: R₁ is ahydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, such asthe methyl or ethyl radical in particular, or an α-tocopheryl radical;and

R₂ is a hydrogen atom or an alkyl radical having from 1 to 4 carbonatoms, such as a methyl or ethyl radical in particular, or R₂ O is anoxyethylene chain of the formula ##STR6## in which R₃ and R₄independently are a hydrogen atom or a methyl radical and n is aninteger greater than or equal to 1,

or a salt thereof, for preparing a pharmaceutical, dermatological orcosmetic composition for the prevention or treatment of allergicmanifestations such as skin allergy or bronchial asthma, or inflammatorymanifestations, or for the prevention or treatment of the harmfuleffects of free radicals.

Thus the products used according to the present invention areα-tocopherol phosphates or esters thereof, it being possible for theseproducts to take the form of cosmetically, dermatologically orpharmaceutically acceptable salts such as, for example, alkali metalsalts, especially sodium salts (monosodium or disodium salt), oralkaline earth metal salts, especially magnesium salts, or else ammoniumsalts or salts of primary, secondary or tertiary amines such as, inparticular, diethylamine, diethanolamine, triethylamine ortriethanolamine.

In formula (I) the alkyl radicals can have a linear or branched chain.

An alkyl radical having from 1 to 4 carbon atoms is for example methyl,ethyl, propyl, isopropyl or butyl, preferably methyl or ethyl.

α-Tocopheryl radical is understood as denoting the radical ##STR7## WhenR₂ O is an oxyethylene chain, n will generally be greater than or equalto 1, for example between 2 and 50, preferably between 2 and 25 and inparticular equal to 2 or 5.

In another advantageous embodiment according to the invention, acompound of formula I as defined above, preferably as a salt, is used inthe form of small liposome-type vesicles obtained by dispersing saidcompound or said salt in water or in an aqueous medium such as a buffersolution, especially by means of mechanical stirring followed byhomogenization, for example with the aid of ultrasound or a homogenizerunder pressure.

Preferably, the size of these vesicles is adjusted to a value of betweenabout 6.10⁻² μm and 2 μm by modifying the homogenization parameters suchas the energy and the duration.

In an advantageous variant of the previous embodiment, theabove-mentioned aqueous medium contains a biologically active agent,said agent being at least partially encapsulated after dispersion in theabove-mentioned vesicles.

Preferably, the above-mentioned active agent is an antiallergicsubstance such as an extract of Scutellaria, for example an extract ofthe root of Scutellaria Baicalensis Georgi described in French patentapplication A-2 628 317, or an antiinflammatory substance.

In an advantageous embodiment of the use according to the invention, theconcentration by weight of the compound of formula (I) mentioned above,or a salt thereof, is between 0.001 and 10%, preferably between 0.01%and 1% and particularly preferably between 0.05 and 0.5%, relative tothe total weight of the composition.

In a currently preferred embodiment, the compound of formula (I)mentioned above is dl-α-tocopherol phosphate. The preferred salts arethe monosodium salts and the disodium salt.

The compounds used according to the invention are generally commerciallyavailable and can be prepared especially by following proceduresdescribed in the literature, for example in Chem. Pharm. Bull. (1971)19, (4), pages 687 to 695; Khim.-Pharm. Zh. (1983) 17, (7), pages 840 to844; Khim.-Pharm. Zh. (1985) 19, (1), pages 75 to 77, or else in U.S.Pat. No. 2,457,932 or Japanese patent 54-54 978.

According to a second feature, the present invention covers a cosmeticor dermatological composition which comprises, as the active ingredient,at least one compound of formula (I) or a salt thereof, as definedabove.

In an advantageous embodiment, the cosmetic or dermatologicalcomposition comprises, as the active ingredient, at least one compoundof formula (I) as defined above, preferably as a salt, in the form ofsmall liposome-type vesicles obtained by dispersing said compound orsaid salt in water or in an aqueous medium such as a buffer solution,especially by means of mechanical stirring followed by homogenization,for example with the aid of ultrasound or a homogenizer under pressure.

Preferably, the size of these vesicles is adjusted to a value of betweenabout 6.10⁻² μm and 2 μm by modifying the homogenization parameters suchas the energy and the duration.

In an advantageous variant of the previous embodiment, theabove-mentioned aqueous medium contains a biologically active agent,said agent being at least partially encapsulated after dispersion in theabove-mentioned vesicles.

Preferably, the above-mentioned active agent is an antiallergicsubstance such as an extract of Scutellaria, for example an extract ofthe root of Scutellaria Baicalensis Georgi described in French patentapplication A-2 628 317, or an antiinflammatory substance.

In another advantageous embodiment, said cosmetic or dermatologicalcompositions are prepared for the prevention and treatment of allergicmanifestations such as skin allergy or bronchial asthma, or inflammatorymanifestations, or for the prevention or treatment of the harmfuleffects of free radicals.

The concentration of active ingredients in these cosmetic ordermatological compositions is as described above for their use.

The compositions according to the invention can be formulated in anyform acceptable for their use in cosmetology, dermatology or pharmacy.In particular, they can be in the form of a preventive and curative skinallergy cream, a soothing antiallergic cream, a soothing antiallergicoil, a preventive or curative antiallergic lotion, an alcoholicaftershave lotion for soothing skin irritations, a hypoallergenic creamor a colloidal antiasthmatic solution, or else in the form of a solutionfor controlling the toxic effects of the superoxide radicals which areformed as a result of intensive care techniques using oxygen.

The compositions according to the invention can also be formulated asmake-up compositions such as make-up foundation, lipstick, mascara andpigmented powder.

According to a third feature, the present invention covers a method ofreducing the allergic or irritant potential of a pharmaceutical,dermatological or cosmetic composition, which consists in incorporatinginto said composition an effective amount of at least one compound offormula (I) or at least one salt thereof, as defined above.

In a currently preferred embodiment, the compound of formula (I)mentioned above is dl-α-tocopherol phosphate. The preferred salts arethe monosodium salts and the disodium salt.

Advantageously, the concentration of compound of formula (I) or saltthereof is as described above for its use.

According to a fourth feature, the present invention further relates toa process for the manufacture of a cosmetic or dermatologicalcomposition intended in particular for the prevention or treatment ofallergic manifestations such as skin allergy, or inflammatorymanifestations, or for the prevention or treatment of the harmfuleffects of free radicals, which comprises incorporating a compound offormula (I) or a salt thereof, as defined above, into a cosmetically ordermatologically acceptable excipient, vehicle or carrier.

According to a fifth feature, the present invention further covers aprocess for the manufacture of a pharmaceutical composition for theprevention or treatment of allergic manifestations such as bronchialasthma, or inflammatory manifestations, or for the prevention ortreatment of the harmful effects of free radicals, which comprisesincorporating a compound of formula (I) or a salt thereof, as definedabove, into a pharmaceutically acceptable excipient, vehicle or carrier.

The incorporation of the compound of formula I or a salt thereof intosaid cosmetic, dermatological or pharmaceutical composition can beeffected by different methods accessible to those skilled in the art,depending on the desired type of formulation.

In an advantageous mode of carrying out said manufacturing processes,when the composition comprises an aqueous phase, the compound of formula(I) mentioned above is first dispersed, preferably in the form of a saltas already defined, in water or in said aqueous phase to form smallvesicles, and the resulting dispersion is then mixed with the otherpossible constituents of the composition.

According to a sixth feature, the present invention covers a method ofpreventing or treating allergic manifestations such as skin allergy orbronchial asthma, or inflammatory manifestations, or of preventing ortreating the harmful effects of free radicals, which comprises applyingan effective amount of at least one compound of formula (I) or a saltthereof, as defined above, incorporated in a cosmetically,dermatologically or pharmaceutically acceptable excipient, vehicle orcarrier.

The invention will now be illustrated in detail with the aid of severalpractical Examples, which are given simply by way of illustration andcannot in any way limit the scope of the invention.

Unless indicated otherwise, the percentages are given by weight in theExamples.

EXAMPLE 1 a) Preparation of a Suspension of Monosodium dl-α-tocopherolPhosphate

0.8 g of powdered disodium dl-α-tocopherol phosphate, obtained by themethod described by P. KARRER (Helv. Chim. Acta (1940) 23, 1137-8), isweighed out.

This powder is poured into 96.2 g of double-distilled water, withstirring, and stirring is continued for about 2 hours.

The mixture is then homogenized by ultrasound for 10 min at 150 W untila clear suspension is obtained, which gives rise to the production ofliposome-type vesicles of disodium tocopherol phosphate.

Where larger volumes are involved, a homogenizer under pressure canadvantageously be used, for example a homogenizer of the Manton-Gaulin®type at a pressure of about 500 bar.

The pH is subsequently lowered to 7 by the addition of about 3 ml of0.5N HCl, with stirring, and then adjusted to 6.5 by the addition of0.1N HCl, with stirring. At this pH the tocopherol phosphate is now inthe form of the monosodium salt.

The resulting size of the vesicles of monosodium α-tocopherol phosphatecan be determined for example by means of an Autosizer 2C from MALVERN.The average size measured in this Example is of the order of 100 nm.

It will also be noted that various dilutions can be made by modifyingthe amount of compounds added at the start or by modifying the volume ofthe dispersion solution, which represents an easy method of preparingvarious concentrations of active principle.

The Example described gave about 100 g of suspension containing about0.8% of monosodium dl-α-tocopherol phosphate in the form ofliposome-type vesicles of substantially homogeneous sizes.

b) Preparation of a gelled composition of monosodium α-tocopherolphosphate

The homogenized suspension obtained above can be gelled by mixing with agel such as a vinylic polymer gel, in particular the one marketed underthe tradename Carbopol® 940.

In a manner known per se, this gel can be prepared for example bydispersing 1 g of Carbopol® 940 in 99 g of water in the presence of apreservative, and then, after swelling, by neutralizing to pH 7.5, forexample with triethanolamine.

100 g of this gel are added to the 100 g of homogenized suspensionobtained above to give a gelled composition having a monosodiumα-tocopherol phosphate concentration of about 0.4%.

Gelled compositions having various α-tocopherol phosphate concentrationscan be obtained by the method indicated above.

EXAMPLE 2 Demonstration of the Antiallergic Activity and Anti-freeRadical Activity of the Compositions According to the Invention A.ANTIALLERGIC ACTIVITY

The purpose of this study is to demonstrate antiallergic effects on theskin after sensitization with DNFB (2,4-dinitro-1-fluorobenzene).

a) Experimental protocol

64 female BalB/C mice, having essentially the same weight and showing nodetectable signs of allergy, are divided up into eight groups of eightanimals.

Group no. 1 receives only DNFB.

Group no. 2 receives only isotonic solution and a non-irritant dose ofDNFB.

Groups no. 3 to 8 receive a test product after sensitization with DNFB,the test products being respectively as follows:

Group no. 3: gel of monosodium dl-α-tocopherol phosphate (TP.Na)according to the invention

Group no. 4: gel of dl-α-tocopherol (α-toco)

Group no. 5: gel of dl-α-tocopherol acetate (Ac-toco)

Group no. 6: gel of polyethoxylated d-α-tocopherol succinate (Vit. ETPGS)

Group no. 7: gelled excipient of α-toco and Ac-toco (T1)

Group no. 8: gelled excipient of TP.Na and Vit. E. TPGS (T2)

The procedure is more precisely as follows:

1) Preparation of the test products

The concentration of each substance is determined so that the testproducts are equimolar in respect of tocopherol.

a) Gel containing 0.128% of Bonosodium dl-α-tocopherol phosphate (TP.Na)according to the invention

This gel is prepared as indicated in Example 1.

b) Gel containing 0.1% of dl-α-tocopherol (α-toco)

0.1 g of α-toco is dissolved in 49.9 g of absolute ethanol. The solutionis stirred at room temperature and then mixed with 50 g of Carbopol® 940gel.

c) Gel containing 0.109% of dl-α-tocopherol acetate (Ac-toco)

0.109 g of Ac-toco is dissolved in 49.891 g of absolute ethanol and thesolution is then mixed with 50 g of Carbopol® 940 gel.

d) Gel containing 0.357% of Vit. E TPGS (polyethylene glycol 1000d-α-tocopherol succinate)

0.357 g of Vit. E TPGS is dissolved in 49.643 g of double-distilledwater. The solution is heated at 70° C., with stirring, untildissolution is complete (about 15 min). It is left to return to roomtemperature (the solution remains clear). 50 g of Carbopol® 940 gel arethen added.

e) Gelled excipient of α-toco and Ac-toco (T1)

This excipient is a 50/50 mixture of absolute ethanol and Carbopol® 940gel.

f) Gelled excipient of TP.Na and Vit. E TPGS (T2)

This excipient is a 50/50 mixture of double-distilled water andCarbopol® 940 gel.

2) Sensitization with DNFB

On day D-0 groups 1 and 3 to 8 receive, by injection into a paw, asensitizing dose of 55 μl of a 1% solution of DNFB in absolute ethanol,diluted two-fold with Freund's adjuvant.

Group no. 2 receives isotonic solution under the same conditions.

3) Application of the products

From day D-1 to day D-7 groups no. 3 to 8 receive a daily application of100 μl of test product deposited on the inside of the right ear and thenspread delicately over both sides of the ear with the aid of a syringe.

On day D-7 this application is made 1 h 30 min after the initiatingadministration of DNFB described below.

4) Initiating administration of DNFB

On day D-7 groups 1 to 8 receive, on both sides of the right ear, anon-irritant initiating dose of 100 μl of a 0.1% solution of DNFB inabsolute ethanol.

5) Development of the antiallergic effect

24 hours after the initiating application of DNFB, the animals aresacrificed and the right ears are delicately removed and then weighed.

b) Results

The results obtained have been reported in Table I below.

This Table contains the mean weight (M) of the right ears for eachgroup, the standard deviation (e) of M and the percentage protection (P)against the action of DNFB.

The percentage protection P was calculated using the formula ##EQU1## inwhich: M₁ is the mean weight for group 1 (DNFB),

M₂ is the mean weight for group 2 (isotonic solution), and

M_(p) is the mean weight for groups 3 to 8 (test products).

The comparison of the results was evaluated statistically by means ofthe Student test:

(S₁): between groups 3 to 8 and group 1 (DNFB--positive control)

(S₂): between groups 3 to 8 and group 2 (isotonic solution--negativecontrol).

                  TABLE I                                                         ______________________________________                                                      M    e        P %    S.sub.1                                                                             S.sub.2                              ______________________________________                                        Group 1 (DNFB)  161.7  12.4                                                   Group 2 (iso. sol.)                                                                           133.7  9.6                                                    Group 3 (TP.Na) 144.0  16.4     +63.2                                                                              s     ns                                 Group 4 (α-toco)                                                                        173.5  18.8     -42.1                                                                              ns    s                                  Group 5 (Ac-toco)                                                                             161.8  12.5     -0.3 ns    s                                  Group 6 (Vit. E TPGS)                                                                         161.8  7.7      -0.3 ns    s                                  Group 7 (T1)    159.8  18.2     +6.7 ns    s                                  Group 8 (T2)    152.7  19.9     +32.1                                                                              ns    s                                  ______________________________________                                         s: significant                                                                ns: not significant                                                      

It can be seen from Table I that the edema caused by the action of DNFBis significantly reduced by the product according to the invention(TP.Na), whereas in this model the comparative products, in particulardl-α-tocopherol and dl-α-tocopherol acetate, have no influence or haveeven increased the reaction caused by DNFB.

The antiallergic activity of the compounds according to the invention istherefore particularly high and surprising, especially in view of thenegative activity of tocopherol.

Various Examples of topical, dermatocosmetic or pharmaceuticalcompositions, especially dermatological compositions, are given below.

B. Study of the anti-free radical activity

This study is performed according to the protocol described by M. S.NOEL-HUDSON, C. de BELILOVSKI, N. PETIT, A. LINDENBAUM, J. WEPIERRE inTOXIC. in vitro, 1989, 3, (2), 103-109.

Tests are carried out on cultures of human keratinocytes. The stocksolution of the test product according to the invention is a 0.1%aqueous solution of disodium dl-α-tocopherol phosphate. This solution isused at different dilutions in MCDB153 culture medium (Irvine®)supplemented with ethanolamine, phosphoethanolamine, cortisone, insulinand calcium (0.1 mM), so as to give the following concentrations ofdl-α-tocopherol phosphate salt: 10⁻³ %, 5.10⁻⁴ %, 10⁻⁴ % and 5.10⁻⁵ %.

The test dilution is brought into contact with the culture cells for 48hours just after inoculation.

The culture medium is then discarded and the cells are rinsed withphosphate buffer. The hypoxanthine/xanthine oxidase system (HX-XO),which is a free radical generator, is then applied for 2 hours 30minutes. After a further rinse with phosphate buffer, the cytotoxicityis determined by the so-called neutral red method (Borenfreund andPuerner, 1985).

The values shown in Table II represent the cell viability expressed asthe percentage of living cells relative to the total number of cells inthe culture in question.

                  TABLE II                                                        ______________________________________                                                Concentrations of the test product                                            0%     10.sup.-3 %                                                                           5.10.sup.-4 %                                                                          10.sup.-4 %                                                                         5.10.sup.-5 %                           ______________________________________                                        Control cultures                                                                        100      66.40   87.92  94.28 100                                   Treated   10.57    39.59   32.79  12.19 9.28                                  cultures (HX-XO)                                                              ______________________________________                                    

It is seen that the percentage cell viability is very considerablyimproved in the cultures which have been in contact with the productaccording to the invention prior to treatment with the HX-XO system,compared with that of the culture to which no product has been addedbeforehand.

This very clearly shows the preventive protective activity of theproduct according to the invention against the cytotoxic action of freeradicals such as those produced by the hypoxanthine/xanthine oxidasesystem.

EXAMPLES OF PHARMACEUTICAL OR COSMETIC FORMULATIONS CONTAINING VITAMIN EPHOSPHATE EXAMPLE 3 Preventive and Curative Skin Allergy Cream

    ______________________________________                                        Composition:                                                                  ______________________________________                                        A -      Cera bellina       5.00   g                                                   Silicone 200       1.50   g                                                   Squalane           5.00   g                                                   Myglyol 812        5.00   g                                                   Nylon 12 SP 500    3.00   g                                                   BHT                0.05   g                                          B -      Demineralized water                                                                              49.56  g                                                   EDTA               0.10   g                                                   Propylene glycol   4.00   g                                                   Carbopol ® 1342                                                                              0.45   g                                                   Triethanolamine    0.54   g                                                   0.4% dispersion of mono-                                                                         25.00  g                                                   sodium dl-α-tocopherol                                                  phosphate, pH 6.6                                                    C -      Germaben II ®  0.80   g                                          ______________________________________                                    

Procedure: Mixture A is heated, with stirring, to give a homogeneousmixture. Mixture B is prepared by dispersing the Carbopol® 1342 in anaqueous solution containing the EDTA and the propylene glycol in 49.56 gof distilled water, and neutralizing with the triethanolamine. The 0.4%dispersion (non-gelled) of dl-α-tocopherol phosphate, obtained accordingto Example 1, is then added.

Mixture B is then heated to 75° C. and held at this temperature, withstirring, while mixture A is added. The resulting mixture is left tocool to 45° C., the Germaben II® is then added and the mixture is leftto cool further to room temperature, with stirring.

This gives a cream.

EXAMPLE 4 Soothing Antiallergic Cream

    ______________________________________                                        Composition:                                                                  ______________________________________                                        A -      Soya lecithin      2.00   g                                                   Cosbiol ®      8.50   g                                          B -      Demineralized water                                                                              58.85  g                                                   EDTA               0.10   g                                                   Glycerol           4.00   g                                                   Carbopol ® 940 0.35   g                                                   Triethanolamine    0.40   g                                                   Germaben II ®  0.80   g                                          C -      0.4% dispersion of mono-                                                                         25.00  g                                                   sodium α-tocopherol                                                     phosphate, pH 6.6                                                    ______________________________________                                    

Procedure: The Cosbiol® and the lecithin are heated, with stirring,until they have completely dissolved, and the solution is left to coolto room temperature. Mixture B is obtained by dispersing the Carbopol®940 in the mixture water+EDTA+glycerol. The whole is neutralized withthe triethanolamine, after which the Germaben II® is added.

Mixture A is then poured into mixture B, with stirring. The resultingmixture is homogenized and the dispersion obtained as in Example 1 isthen added. The mixture is homogenized again to give a cream which canbe applied locally in the morning and evening to soothe allergic skinreactions.

EXAMPLE 5 Soothing Antiallergic Oil

0.1 g of powdered disodium α-tocopherol phosphate is dissolved in 99.9 gof trioctyl citrate at 70° C. for 8 h, with magnetic stirring.

The resulting oily solution can be applied locally, like the cream ofExample 4.

EXAMPLE 6 Alcoholic Aftershave Lotion

    ______________________________________                                        Composition:                                                                  ______________________________________                                        Disodium α-tocopherol                                                                          0.2    g                                               phosphate                                                                     Ethanol                40     g                                               Propylene glycol       0.5    g                                               Pantothenol            0.1    g                                               Perfumed aqueous       100    g                                               excipient qsp                                                                 ______________________________________                                    

Preparation: The disodium tocopherol phosphate is dissolved in theabsolute alcohol, and the other constituents are dissolved in the waterto give a separate solution. The two solutions obtained are mixed andthe whole is homogenized by means of ultrasound.

This lotion makes it possible to soothe the irritations due to shaving,which are commonly referred to as "smarting".

EXAMPLE 7 Preventive or Curative Antiallergic Lotion

    ______________________________________                                        Composition:                                                                  ______________________________________                                        4% dispersion of mono-                                                                              25.00   g                                               sodium α-tocopherol                                                     phosphate                                                                     Ethanol               10.00   g                                               Propylene glycol      5.00    g                                               Aqueous excipient qsp 100.00  g                                               ______________________________________                                    

The 4% dispersion of α-tocopherol phosphate is prepared as in Example 1,except that this dispersion has a greater concentration of monosodiumα-tocopherol phosphate.

The constituents of the above formulation are mixed together andhomogenized by means of ultrasound.

EXAMPLE 8 Colloidal Antiasthmatic Solution

    ______________________________________                                        Composition:                                                                  ______________________________________                                        4% dispersion of mono-                                                                              12.50   g                                               sodium α-tocopherol                                                     phosphate                                                                     Buffered aqueous      100.00  g                                               excipient + preservative                                                      qsp                                                                           ______________________________________                                    

The dispersion of monosodium tocopherol phosphate is prepared as inExample 1. After homogenization with ultrasound, a colloidal solution isobtained which is then incorporated into the buffered excipient.

This solution can be used as a spray in the upper respiratory tract,especially for soothing asthmatic coughs.

EXAMPLE 9 Colloidal Solution for Intensive Care Techniques

    ______________________________________                                        Composition:                                                                  ______________________________________                                        4% dispersion of mono-                                                                              7.50    g                                               sodium α-tocopherol                                                     phosphate                                                                     Buffered aqueous      100.00  g                                               excipient + preservative                                                      qsp                                                                           ______________________________________                                    

This composition is prepared as in the previous Example.

It can be used for controlling the toxic effects of the superoxideradicals which are formed as a result of intensive care techniques usingoxygen. In this case it is administered as an intratracheal instillationat the same time as the gaseous mixture is administered.

EXAMPLE 10 Antiallergic Make-up Foundation

    ______________________________________                                        Composition:                                                                  ______________________________________                                        Disodium dl-α-tocopherol                                                                       0.5    g                                               phosphate                                                                     Emulsion for make-up   99.5   g                                               foundation                                                                    ______________________________________                                    

This composition is prepared by incorporating the disodium tocopherolphosphate, previously dispersed in water, into the aqueous phase of theemulsion. The emulsion is then prepared by the conventional procedure.

This make-up foundation minimizes the risks of allergic manifestationsdue to a raw material or to an allergenic substance coming into contactwith the skin.

What we claim is:
 1. A method for lowering the allergic capacity orirritating capacity of a cosmetical or pharmaceutical composition havingthe propensity to cause an allergic reaction, comprising incorporatingin that composition an efficient mount of a tocopherol compound selectedfrom the group consisting of:a) a alpha-tocopherol compound of thefollowing general formula (I) ##STR8## wherein: R1 represents a hydrogenatom, an alkyl radical having from 1 to 4 carbon atoms, or aalpha-tocopheryl radical, R2 represents a hydrogen atom, an alkylradical having from 1 to 4 carbon atoms, or R2O represents anoxyethylenated chain, of formula ##STR9## wherein R3 and R4 representsindependently a hydrogen atom or a methyl radical, and n represents aninteger number higher or equal to 1, b) a DL form of said tocopherolcompound of formula (I), c) a D form of said tocopherol compound offormula (I), d) a cosmetically or pharmaceutically acceptable ester ofsaid tocopherol compound of formula (I) e) a cosmetically orpharmaceutically acceptable salt of said tocopherol compound of formula(I),said tocopherol defined above compound being optionally incorporatedin a cosmetically or pharmaceutically acceptable excipient.
 2. Themethod of claim 1, wherein said compound of formula (I) is incorporatedin said composition in a weight concentration ranging from 0.001 to 10%with respect to the total weight of said composition.
 3. The method ofclaim 1, wherein said compound of formula (i) is DL-alpha-tocopherolphosphate.
 4. The method of claim 1, wherein said salt of compound offormula (I) is selected from a monosodium salt and a disodium salt. 5.The method of claim 1, wherein said tocopherol compound of formula (I)is in the form of small vesicles of the liposomal type dispersed inwater or aqueous medium.
 6. The method of claim 5 wherein a cosmeticallyor pharmaceutically acceptable salt of said tocopherol compound offormula (I) is used.
 7. The method of claim 5 wherein the size of saidvesicles ranges between 6.10×10⁻² micrometers and 28 micrometers.
 8. Themethod of claim 5 wherein said aqueous medium contains a biologicallyactive agent, said agent being encapsulated in said vesicles.
 9. Themethod of claim 8 wherein said biologically active agent is ananti-allergic substance.
 10. The method of claim 9 wherein saidanti-allergic substance comprises a Scutellaria extract.
 11. The methodof claim 10 wherein said Scutellaria extract is an extract from theroots of Scutellaria.
 12. The method of claim 8 wherein saidbiologically active agent is an anti-inflammatory substance.
 13. Themethod of claim 1 whereto said allergic reaction is selected from thegroup consisting of a cutaneous allergy and bronchial asthma.
 14. Themethod of claim 10 wherein said anti-allergic substance is an extractfrom Scutellaria Baicalensis Georgi.
 15. The method of claim 14 whereinsaid Scutellaria extract is an extract from the roots of ScutellariaBaicalensis Georgi.
 16. A method of prevention or of treatment ofinflammatory reactions due to allergic reactions, comprising treating asubject concerned by said inflammatory reactions due to said allergicreactions with an efficient amount of:(a) an alpha tocopherol compoundof the following general formula (I) ##STR10## wherein: R₁ represents ahydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, or analpha tocopheryl radical; R₂ represents a hydrogen atom, and alkylradical having 1 to 4 carbon atoms, or R₂ O represents an oxyethylenatedchain having the formula: ##STR11## wherein R₃ and R₄ representindependently a hydrogen atom or a methyl radical, and n represents aninteger of 1 or more; (b) a DL form of said tocopherol compound ofFormula (I); (c) a D form of said tocopherol compound of Formula (I);(d) a cosmetically or pharmaceutically acceptable ester of saidtocopherol compound of Formula (I); (e) a cosmetically orpharmaceutically acceptable salt of said tocopherol compound of Formula(I);said tocopherol compound defined above being optionally incorporatedin a cosmetically or pharmaceutically acceptable excipient.
 17. Themethod of claim 16, wherein said tocopherol compound of formula (I) isin the form of small vesicles of the liposomal type dispersed in wateror aqueous medium.
 18. The method of claim 17 wherein a cosmetically orpharmaceutically acceptable salt of said tocopherol compound of formula(I) is used.
 19. The method of claim 17 wherein the size of saidvesicles ranges between 6.10×10⁻² micrometers and 28 micrometers. 20.The method of claim 17 wherein said aqueous medium contains abiologically active agent, said agent being encapsulated in saidvesicles.
 21. The method of claim 20 wherein said biologically activeagent is an anti-allergic substance.
 22. The method of claim 21 whereinsaid anti-allergic substance comprises a Scutellaria extract.
 23. Themethod of claim 22 wherein said Scutellaria extract is an extract fromthe roots of Scutellaria.
 24. The method of claim 20 wherein saidbiologically active agent is an anti-inflammatory substance.
 25. Themethod of claim 16 wherein said compound of Formula (I) is incorporatedin a cosmetically or pharmaceutically acceptable excipient to constitutea composition, said compound of Formula (I) being present in a weightconcentration ranging from 0.001 to 10% with respect to the total weightof the composition.
 26. The method of claim 16 wherein said compound ofFormula (I) is DL-alpha tocopherol phosphate.
 27. The method of claim 16wherein said compound of Formula (I) is selected from a monosodium saltand a disodium salt.
 28. The method of claim 16, wherein said allergicreaction is selected from the group consisting of cutaneous allergy andbronchial asthma.
 29. The method of claim 22 wherein said Scutellariaextract is an extract from Scutellaria Baicalensis Georgi.
 30. Themethod of claim 29 wherein said Scutellaria extract is an extract fromthe roots of Scutellaria Baicalensis Georgi.